Introduction: Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective is to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. Material and methods: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous Superficial Spreading Melanoma, and Nodular Melanoma with at least five years of follow-up. Results: Most morphological and immunohistochemical features show statistically significant differences between the two cell lines. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (P=0.000) and reduced the number of metastases (P=0.004). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT+MSCs in the A357 tumor cell line, and 89.84% RT+MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation, the number of metastases, and reduced expression of adhesion molecules. Discussion/Conclusions: The combined treatment of RT+MSCs on xenografted melanomas reduces tumor size, metastases frequency and the EMT/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin) and molecules related with prognosis (IMP3).